Generally, diabetes mellitus is a globally occurring adult disease. Recently, the occurrence rate of diabetes mellitus in Korea has reached 10%, and the global diabetes mellitus population has already passed 240 million. According to a report by the Journal of the American Medical Association (JAMA) in 2009, the number of diabetics globally is expected to grow to 380 million, and among them, about 60% of the diabetes mellitus cases will occur in Asian regions. In particular, the onset of diabetes mellitus has advanced to young adults, and the occurrence of complications has become unavoidable due to extended life expectancy.
Diabetic retinopathy occurs in diabetics within 10 years from the onset of diabetes mellitus with a probability of 60% or higher, and within 20 years with a probability of 90% or higher. Particularly in Korea, the medical expenses for the treatment of peripheral circulatory disorders, which are diabetic complications, has increased from 80.7 billion Korean won in 2006 to 153 billion Korean won, and the expenses for diabetic retinopathy have increased from 32.7 billion Korean won to 50.5 billion Korean won, showing a 54.4% increase. Diabetic retinopathy is a type of microangiopathy caused by chronic diabetes mellitus, and is characterized by having an altered permeability and vaso-occlusion of retinal blood vessel, change in ischemia, neovascularization, and subsequent fibrovascular proliferation. Diabetic retinopathy is the most frequent cause of postnatal blindness in adults, and about 12,000 to 24,000 people in the USA become blind due to diabetes mellitus every year. In fact, a laser treatment or a surgery of vitreous body is not sufficient to end the progression of blindness and about 8% of the treated diabetics ultimately become blind. Accordingly, early discovery of diabetic retinopathy, prevention of the progression of diabetic retinopathy, and early treatment are essential, but the exact etiology of diabetic retinopathy still remains unknown and thus its effective treatment is limited.
More than 80% of diabetic neurosis occurs in diabetic patients due to accumulation of metabolic side products, myelin loss in neurons, and changes in microvessels. Generally, the treatment of neurosis cannot be easily performed, and thus its prevention by regulation of blood glucose level or alleviation of symptoms such as pain is often performed instead.
Peripheral vascular disease can be discovered in 45% of patients after a duration of about 20 years of diabetes mellitus since its onset, which normally accompanies arterial stiffness and circulatory disturbance, and its complete cure is difficult. For example, foot ulcer is a dreadful complication which requires surgical removal of the four limbs.
Diabetic nephropathy patients require hemodialysis due to improper renal functions caused by chronic diabetes mellitus, and may ultimately require kidney transplantation.
Chronic diabetes mellitus causes functional disorders in blood vessels and lymphatic ducts, thereby releasing tissue fluids and blood or making them stagnant. When these symptoms appear in the retinal blood vessels, there occur macular edema and macular degeneration due to an abnormal change in drusen, etc., whereas when this symptom occurs in veins there occur varices; when these symptoms occur in lymphatic ducts there occurs lymphedema; and when these symptoms occur histologically in lower limbs there occur varicose veins. Accordingly, these are accompanied by visual impairment, blindness, lower limb numbness, pain, paresthesia, and nocturnal pain. However, there is no therapeutic agent available and thus only pharmaceutical drugs similar to antioxidants are being administered (Diabetes, the 4th edition, Korean Diabetes Association, Korea Medical Book Publisher, 2011, p. 577).
For the treatment of macular degeneration, high-priced intravitreal antivascular endothelial growth factor therapy or laser therapy may be used, but these therapies still cannot cure the disease and thus the patients must tolerate fatal visual impairment.
Meanwhile, the formation of advanced glycation endproducts (AGEs) is one of the representative factors in inducing diabetic complications. Nonenzymatic glycation of proteins is a reaction for producing advanced glycation endproducts (AGEs) by a condensation reaction (Maillard reaction) between an amino group such as a lysine residue of a protein and a reducing sugar, without an enzymatic reaction. Unlike the reversible Amadori type early glycation products, the advanced glycation endproducts are irreversible reaction products. Therefore, once the advanced glycation endproducts are produced, they are not decomposed but accumulated in tissues during the lifetime of the proteins, although the blood glucose level returns to normal, thereby abnormally changing the structures and functions of the tissues and inducing complications such as diabetic retinopathy, diabetic cataract, diabetic nephropathy, diabetic neuropathy, diabetic cancer, diabetic heart disease, diabetic osteoporosis, foot ulcer or diabetic arteriosclerosis, etc. (Vinson, J. A. et al., 1996, J. Nutritional Biochemistry 7: 559-663; Smith, P. R. et al., 1992, Eur. J. Biochem., 210: 729-739).